Synthesis, characterization and utilization of a new series of 1,2,3-triazole derivatives to neutralize some toxic activities of Bothrops jararaca snake venom

Abstract Snake envenomation is a public health problem, and while serum therapy prevents death, the local effects of venoms can lead to amputations or morbidities. Thus, alternative treatments deserve attention. In this study, we tested eight derivatives of 1,2,3-triazole against some toxic activities of Bothrops jararaca venom. The derivatives were synthesized, and their structures analyzed by infrared and nuclear magnetic resonance. After that, the ability of compounds to inhibit hemolysis, coagulation, proteolysis, hemorrhaging, edema, and lethal activities of B. jararaca venom was investigated. The derivatives were incubated with B. jararaca venom (incubation protocol), administered before (prevention protocol) or after (treatment protocol) injecting venom into the mice. Then, hemorrhaging assay occurred. As a result, most of the derivatives inhibited the activities, even if they were incubated, injected before or after B. jararaca venom. However, the derivatives TRI 07 and TRI 18 seemed to be the most efficient in impairing hemorrhaging. The derivatives showed a low drug score of toxicity based on an in silico technique. Therefore, the derivatives fulfilled physicochemical and biological requirements to become drugs, and they may be a brand new initiative for designing antivenom molecules to complement antivenom therapy to efficiently block tissue necrosis or any other local effects.

Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1, 4-naphthoquinones through molecular modelling

BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite.

Síntese e atividade antiestafilocócica do derivado 2-acetóxi-1, 4-naftoquinona / Synthesis and anti-staphylococcus activity of 2-acetoxi-1, 4-naftoquinona derivative

O derivado 2-acetóxi-1, 4-naftoquinona (DNQ), sintetizado por Ferreira, foi testado contra seis diferentes espécies de bactérias isoladas de pacientes do Hospital Universitário Antônio Pedro (HUAP). A droga exibiu atividade apenas contra cepas Gram-positivas (zonas de inibição = 12 mm, em testes preliminares): Enterococcus faecalis, Staphylococcus aureus e Staphylococcus epidermidis. Para os isolados de S. aureus, as concentrações mínimas inibitórias (CMIs) e mínimas bactericidas (CMBs) variaram de 16mug a 256 mug/ml e de 64 mug a 512 mug/ml, respectivamente. Através da espectrofotometria de absorção em 560nm, DNQ originou cinéticas de inibição diretamente proporcionais às suas concentrações, com 2CMI promovendo resposta lítica (apenas na 1ª hora de tratamento) nas cepas sensíveis à oxacilina. Em nível de viabilidade celular (UFC/ml), os efeitos do derivado também cresceram na razão direta do aumento de sua concentração, com 2 x CMI acarretando uma resposta bactericida bem nítida (já na 2ª hora de ação), contra as cepas sensíveis ao Beta-lactâmico. Apesar da menor atividade do DNQ em relação aos antibióticos de uso em clínica, estamos continuando os estudos com o derivado, agora, na tentativa de, através da modificação de sua estrutura, ampliar o seu espectro de ação e a sua atividade antibacteriana.

NBS bromination reactions of dihydronaphthofuran quinones: a new fragmentation type reaction in the chemistry of quinones

The reactions of isomeric dilydronaphthofuran-quinones of the alfa ß type, 1 and 5, respectively, with NBS, under visible light, gave products. These reactions represent a new route to structural types represented by naphthol [1,2-b] furan and naphtho [2,3-b] furan quinones and lead to a new assessment of biosynthetic theory concerning the furan ring in plants